21-alkyl-17beta-hydroxy-17alpha-pregn-20-ynes, therapeutic compositions comprising same, and process therefor



United States Patent ZI-ALKYL 17fl-HYDROXY 17a PREGN-ZO-YNES, THERAPEUTIC COMPOSITIONS COMPRISING SAME, AND PROCESS THEREFOR Suzanne Patricia Barton, Derek Burn, George Cooley,

Bernard Ellis, Vladimir Petr-ow, and Isobel Ann Stuart- Webb, all of'London, England, assignors to The British Drug Houses Limited, London, England, a British company it preparation of 21-alkyl derivatives of 17 3-hydroxy-17a f pregn-ZO-ynes, which are of value on account of their progestational properties or :as intermediates in the preparation of compounds with useful progestational properties.

It is an object of the present invention to provide pharmaceutical and veterinary preparations of new 21- alkyl derivatives of 17fi-hydroxy-17a-pregn-20-ynes.

According to the present invention there are provided 21-alkyl derivatives of 17fi-hydroxy-17a-pregn-20-ynes having the general formula where R is an alkyl group containing from 1 to 8 carbon atoms. In particular, the invention provides new 21- alkyl derivatives of 17fl hydroxy-17a-pregn-20-yne having the general formula R1 i t h group containing from 1 to 4 carbon atoms, and R is selected from-the group consisting of where R is an alkyl "W CHI H k/lg and H0 (511 t The new compounds may be 2l-alky1 derivatives at 17p-hydroxy-17a-pregn-4-en-20-yn-3-one, and 17p-hydroxy-6-rnethyl-17a-pregn-4-en-20-yn 3 -one.

2,939,819 Patented June 7, 1960 2 The present invention provides the specific new com pounds a 3 13: 17 8-dihydroxy-21-methyl-17u-pregn-5-en-20-yne,

318: 17fi-dihydroxy-2l-ethyl-l7a-pregn-5-en-20-yne,

6 B 21-dimetnyl-17 a-pregn-20-yne-3 {3 5 a1: -triol,

5 oz 17 3-dihydroxy-2 l-ethyl-ofi-methyl- 17a pregn-20-yn-3- one and 6 21-dimethyl-17a-pregn-5-en-20-yne-3fiz 17p-dio1 which are of value as intermediates in the preparation of compounds with useful progestational properties.

The present invention also provides the specific new compounds: i

17B-hydroxy-21-methyl-17a-pregn-4-en-20-yn-3-one, t17,3-hydroxy 21-ethyl-17oz-pregn-4-en-20-yn-3-one, a 6 a 2 1-di1nethyl-17 8-hydroxy-17ct-pregn-4-en-2o-yn-3 one, 21-ethyl-17F3-hydroXy-6a-methyl-17apregn-4-en 20-yn-3- one s t which are of value on account of their progestational properties. 6a:2l-dimethyl-l7,8-hydroxy-17 -pregn-4-en- 20-yn-3-one and 21-ethyl-17fi-hydroxy-6a methyl 17apr egn-4-en-20-yn-3-one, are particularly noteworthy in this respect being found to be circa 12 and'circa9 times more efiective than is ethisterone when. administered by the. oral route in the Clauberg assay. Theyconsequently find application in the treatment of symptoms arising from the syndrome known as premenstrual tension. They may also be used to counteract the over-oestrinisation occurring in patients with persistent menorrhagia and to ensure establishment of normal progestational effects in the u-teri of women suffering from secondary amenorrhoea.

According to the present invention there is further provided a process for the preparation of 21-alkyl deriva tives of 17p-hydroxy-17a-pregn-20-ynes having the general formula a i Me 0H from l7fl-hydroxy-17a-pregn-20-ynes having thegener al formula the general Formula Il may be conveniently elfected by condensation with vinylic ethers such as, for example,

isopropylvinyl ether or 2:3-dihydropyran. 2-: 3-dihydro- (III) may conveniently be effected by mixing the compound of Formula II with an excess of 2:3-dihydropyran, preferablyin'anorganic solvent such as chloroform or tetrahydrofuran, .anda'in the presence of a catalytic quantity of an acidic reagent such as, for example, hydrochloric acid or phosphorus oxychloride. Purification of the resulting tetrahydropyranyl ether of general Formula III is generally unnecessary andthe crude material may be .useddirectly for the next stage of the process.

.21.:alkylation of the tetrahydropyranyl ether of general formula III may be achieved by converting com-' pound *I-II into a C -metallic derivative and condensing thelatter with e.g. an alkyl halide or sulphate to give mula Lithium, sodium and potassium derivatives of the compound III are very .suitable for this purpose. Their formation is readily efiected by adding the compound III to a solution of the metal amide in liquid ammonia. Thus, for example, the compound III may be dissolved in a solvent such as ether and the solution added to lithamide, sodamide or potassamide in liquid ammonia when conversion to the metal derivative takes place. .alkyl:halide,.-such :as for example, ethyl bromide or iodide, is then added to the solution when the 21-211- kylated tetrahydropyranyl ether (IV) is obtained.

Regeneration ofthe 17,8-hydroxylic group from compound IV to give the desired 21-alkyl derivative of a substituted 17(3-hydroxy-l7opregn-20-yne may be effected by methods well known to those skilled in the art. Thus, for example, regeneration of the l7fl-hydroxylic group may be accomplished by treating the 21-alkylated tetrahydropyranyl ether with an acidic reagent, such as for example hydrochloric acid, toluene-p-sulphonic acid or :oxalic acid in a solvent such as ethanol either at room temperature or under reflux conditions depending upon the nature of thesubstituents in the 21-alky1ated tetrahydro'pyranyl ether. 7

fTheprocessof the invention .may be applied to 17 3- hydroxy l7a-pregn-20-ynes (I) containing a variety of substituents and unsaturated linkages in the molecule 'as will The apparent to those skilled in the art. ,Sluch substituents-may include, for example, oxo-, hydroxyl- Katlditionailto the'hy'd'roxyl group at C phenolic-"hy- "droxyh, and methyl-"groups. By way of examples, methods for dealing with such additional unsaturated linkages and substituents will be outlined below:

(i) Isolated unsaturated linkages such as, for example, at 9:11. These do not interfere, in general, with the process of the invention.

(ii) Methyl -,-groups,- such as, jorexample, Me groups 7 at C C C Thesedondt interfere, in :ge'neraljwith the process of theinvention. I I

(iii) Hydroxyl groups such as for example, hydroxyl groups at C Q and C 1 and phenolic j hydroxyl-groups. These are conveniently protected by conversion into the tetrahydropyranyl ethers concurrently with theconversion of the 17,8-hydroxyl group (see Formula II) into the tetrahydropyranyl ether (see Formula III), and subsequently regenerated. Thus, for example, .6fi-methyl-l7upregn-ZO-yne-fifl:,5 -.17/3 trio1 (V) may be converted ,into the w OH OR oson M ----'o 5 on (VII) which may then be Cgfialkylated, for example by the action of ethyl iodide'on its lithium derivative to give the 21-al'kyl tetrahydropyranyl ether which on treatment with dilute ,oxalic acid yields the desired 21-alky1-17e-pregn-20-yne-318:5a:175-triol (VIL) (R=alkyl).

(iv) ,Oxo-groups: jOxo;groups may conveniently ,be protected, for example by 'ketal or enol ether formation, and subsequently regenerated. Thus, for example, 1718- hydroxy-Gwmethyl-l7a-pregn 4-en-20 yn 3-,one -(-VIII) rnay' be converted into the ethylene ketal t x) ('IX; R=R'.==H), which may then be condensed with 2:3edihydropyran to give the ketal tetrahydropyranyl ether a The last compound'is then alkylated to give the 2l-alkyl derivative 1 i i Treatment of this material with dilute .ethanolic oxalic acid leads to regeneration of the l7fi-hydroxyl group and 3-oxo group to give the: desired 21-alkyl-17B-hydroxy- :fid-me'thyl-l7a pregn-4-en-20-yn-3-one (X) (R=alkyl).

The invention also therefore provides aYmethod for the preparation of 21-a1kyl derivatives of l7fi-hydroxy- 17u-pregn-20-ynes having the general Formula I above where R is an alkyl group co'ntainingfrorn 1 to 8 carbon atoms which method comprises converting a 17,9- hydroxy-l7a-pregn-20 yn-3 -one into a 3 :3-ethylenedioxy fderivative, condensing the 3:3-ethylenedioxy derivative with 2:3-dihydropyran to give a l7fi-tetrahydropyranyl etherof the 3:3-ethy1enedioxy derivative, alkylating the 17B-tetrahydropyranyl ether to give a 21-alkyl derivative and treating the 2l-alkyl derivative with diluteethanolic oxalic acid to regenerate the l7fl-hydroxyl group and 3- oxo group and give the desired 21 alkyl-17fi-hydroxy-17w pregn-20-yn-3-one. I

EAMPLE 1 17p3-hydroxy-21-etl yl-17a-pregn-4-en-20-yn-3-one Having the formula aqueous methanol.

was no longer turbid.

6 -Method (a).-A solution of 35:17fl-dihydroxy-17a- .pregn-S-en-ZO-yne (10 g.) in tetrahydrofuran ml.)

was mixed with 2:3-dihydropyran (25 :ml.) followed by phosphorus oxychloride (0.2 ml.). After 2% 1 hours, the mixture was poured into water (2 1.) and the solids obtained, collected and crystallised from aqueous acetone containing a trace of pyridine. The 313:17fl-bis-tetrahydropyranyl ether of 3B:l7B-dihydroxy 17a-pregn-5-en- 20-yne had M.P..173 to 174 C., [al -420 (c, 0.61 in chloroform).

The foregoing compound (4.1 g.) in dry ether '(165 ml.) was added dropwise over 1 hour to a stirred solution of ferric nitrate (0.2 g.) and lithium (0.45 g.) in liquid ammonia ml.) maintained at a temperature between 35' C. and -40 C. After stirring for a further 2% hours, a solution of methyl iodide (11 ml.) in dry ether (50 ml.) was added over 30 minutes and the stin'ing con tinued thereafter for a further 3 hours. Ammonium chloride (5 g.) was added to the mixture, and the ammonia allowed to evaporate. The product, isolated with ether, was triturated with methanol to give material with M.P. to C. This material (400 mg.) in ethanol (50 ml.) was treated with toluene-p-sulphonic acid mg.) and the mixture heated for 30 minutes on the steambath. Concentration followed by the addi tion of water gave a solid which was purified from 3132:1713 dihydroxy 2l-methyl-l7apregn-S-en-ZO-yne formed plates, M.P. 177 to 179 C., [(11 -124 (c, 1.0-in chloroform).

The foregoing compound (1.2 g.) was dissolved in a mixture of toluene (100 ml.) and cyclohexanone (40 ml.) and the solution distilled until 30 ml. of distillate had collected. Aluminium isopropoxide (5 g.) in toluene (20 ml.) was added and the mixture heated under reflux for 1 hour. After washing with dilute sulphuric acid, the solvents were removed by steam-distillation and the product isolated with ether. Its solution in benzene was filtered through a short column of alumina. Purification from a mixture of equal parts of acetone and hexane gave 17fi-hydroxy 21-methyl-17a-pregn-4-en-20-yn-3-one, in micro-needles, M.P. l50-to 151 C., [u] +11 (c, 0.53 in ethanol)! 1" Method (b).-A solution of 17fi-hydroxy517a-pregn-4- en20-yn-3-one (5 g.) in a mixture of benzene (110 ml.) and ethylene glycol (6 ml.) was distilled until the distillate Thereafter, toluene-p-sulphonic acid (0.1 g.) was added, and the mixture heated under reflux for 4 hours. The product which separated on cooling was crystallised from aqueous pyridine to'give 3:3-

ethylenedioxy-l7fi-hydroxy-17a-pregn-5-en-20-yne, in soft plates, M.P. 258 to 259 C., [0:] 69 (c, 0.75 in pyridine). i s

The foregoing compound (3.8 g.) in tetrahydrofuran (200) ml.) was treated with 2:3-dihydropyran (10 m1.)

followed by phosphorus oxychloride (0.08 ml.). After hours, the mixture was poured into diluteaqueous sodium bicarbonate solution, and the precipitated solids purified from aqueous acetone containing a trace of pyridine. The 17,3-tetrahydropyranyl ether of 3:3- ethylenedioxy-l7fi-hydroxy-17oc-pregn-5-en 20 yne had -M.P."" to 174 C., 92 (c, 0.77 in pyridine).

The foregoing compound (4 g.) in dry ttrahydrofuran (100 ml.) was added dropwise over 1 hour to a stirred solution of ferric nitrate (0.2 g.) and lithium (1.55 g.) in

liquid ammonia (400 ml.) maintained at a temperature between -35 C. and 40 C. After stirring for a further 2% hours, a solution of methyl iodide (11 ml.) in dry ether (50 ml.) was added over 30 minutes and the stirring continued thereafter for a further 2% hours. Ammonium chloride (5 g.) was added to the mixture, and the ammonia allowed to evaporate. t The product, isolated with ether, was triturated with ethanol to give .material, with M.P. 145 to 146 C., which was purified from aqueous acetone containing a trace of. pyridine. The 17 :3trtr hydmpyranyl ether of 3:3-ethyleuedioxw 'moved by filtration.

and the ammonia allowed to evaporate.

-1'7/3=hydroxy-2l-methyl-17a-pregn --en 20 yne-for-med needles, MrP. 148 to 149 C., -.84 (0,1 0.99 in pyridine). 1

The foregoing compound 200 mg.) in ethanol ml.) was treated with 2% aqueous oxalic acid (-l0 ml.) and the mixture heated under reflux for 45 minutes. Dilution-with an equal volume of water ml.) gave a small quantity of crystalline material which was relFurther addition of waterto the filtrate gave plates, M.P. 100 C. to 104 C. which was purified from acetone/hexane. 17fi-hydroxy-2l-methyl- 17u-pregn -4 -'en-20-yn-3-one separated in prismatic needles, MP. 151 to 152 C., not depressed on admixture With a specimen prepared by Method (a) above.

EXAMPLE 2 21 -ethyl- 17fi-hydr0xy-1 7 a-pr egn-4-en-20-yn- 3-one (Formula XI) (whereR=C H Method (a).-A solution of the 3,8: l7 fl-bis-tetrahydropyranyl ether of 3B: l7B-dihydroxy-l7a-pregn-5-en-20 yne (6 g.) (prepared as described in Method (at) of Example 1) in dry ether .(100 ml.) was added dropwise oyer l ,hour to a stirred solution of ferric nit-rate (0.3 g.) and lithium (1.1 g.) in liquid-ammonia (200 ml. );maintained at a temperature between and 940 C. After minutes and the stirring continued thereafter for a further -3 hours. Ammonium chloride was added to the mixture, The product,

isolated :with ether, was dissolved in ethanol.,(60 ml.) and heated .under reflux for 30 minutes with toluene-psulphonic acid (0.6 g.) Theproduct was isolated with etherand crystallised from acetone/ hexane, when 33:175- dihydroxy-21-ethyl-17a-pregn-5-en-20eyne separated in fi.n'e needles, M.P. 78 to 80 C., [0011322 107 (c, 0.4

in pyridine)- The fOfiPgoing compound .(1 g.) :Was dissolved in a mixture of toluene (80- ml.) and cyclohexanone (32 ml.)

and the solution distilled until the distillate was nolonger turbid. Aluminium isopropoxide (.4 g.) in toluene (16 .ml.) was added and the mixture heated under reflux for .20 minutes. Theproductwas isolated ;in;the usual way and its solution inbenzenechromatographed on alumina.

i y-l' a-h d x rma eaman. W Gh- 'y5 lised from acetone containing a trace of pyridine, --in need1es,M.P. 12mm 121 3., [6:1 105 (c; 1.01 in pyridine).

The foregoingcompoundQ g.) in. ethanol (200 was heated under reflux with 2% aqueous oxalic acid (100 ml.) for 55 minutes. The product was isolated with ether and its benzene solution filtered through a column of alumina. 2l-ethyl-l7fl-hydroxy l7u-pregn=4 en 2O-yn- 3.-one crystallised from acetone/hexane in plates, M-,P.

118 to 1 19 C., not depressed on admixture with a specimen preparedv by Method (a) above.

EXAMPLE 3 i 2;] -n pr pyl 1 Zfl-hydroxy-I 7 a-pregn:4.-en=20-tyhat-one V (Formula'XI, Where R=n-propyl) a ..Met hod '(a).-A solution of the 3fi:17 3-bis-tetrahydro- .pyranyl etheroffifl: 17fldihydroxy-l7a;pregn#5-en-20-yne l (8 5g.) (prepared. as described in Method 1 (a) of-" Exarnple 1) in dry ether (200 ml:) was added dropwise over 1 hour to a stirred solution of ferric nitrate (0.2 g.) and lithium (1.5 g.) in liquid ammonia (300 m1.) maintained at a temperature between 35 and -40 C. After stirring for a further 2% hours, a solution of n-propyl iodide (13.5 ml.) in dry ether (100 ml.) was added over 30 minutes and the stirring continued thereafter for a further 3 hours. Ammonium chloride was added to the mixture, and the ammonia allowed to evaporate. The product, isolated with ether, was dissolved in ethanol ml.) and heated under reflux for 30 minutes with toluene-psulphonic acid (0.8 g.) The product was isolated with ether and crystallised from ether/petroleum ether, when 3,;8:,1'ZB-dihydroxy-21-n-propyl-17a-pregn- 5 en .20 yne separated in fine needles, M.P. 70 to7 1 0., [1x1 1l0 (c, 1.002 in chloroform).

The foregoing compound (1.2 g.) was dissolved in a mixture of toluene ml.) andcyclohexanone (40 ml.)

and the solution distilled until the distillate was no longer for 20 minutes. The product was isolated in theusual way and its solution in benzene chromatographed on alumina. 21 11-propyl-17/8-hydroxy-17a-pregn-4-en-20-yn- 3-one crystallised from acetone/hexane in long prisms, M.P. 84 to 86 C 7' Method (b) .-The l7 8-tetrahydropyranyl ether of 3:3- ethylenedioxy- 1 7p-hydroxy-17u-pregn-5-en 20.- yne, prepared as described'in Method (b) of Example 1, was npropylated by a procedure similar to the methylation procedure described inMethod b.) of'Example 1, to give the 17fletrahydropyranyl ether of 3:3-ethylenedioxy-17B- hydroxy-2l-n-propyl-l7ot-pregn-5-en-20-yne, which crystallised from acetone containing a trace of pyridine, in needles, M.P. 104 to 106.C., [041 l34 (c, 1.07 in chloroform) J The protective groupings presentin the foregoing compound were removed with aqueous ethanolic oxalic acid underthe conditions described in Method (b) of Example 2, to give 17j3-hYdI'OXY-21-I1rPTOPYl-170t-pI'6gH-4 en' 20-yn- 3-one, which crystallised fiom acetone/hexane in dense prisms, M.P. 86 to 87.-C.,-[0]D27 +8? (c,.0.72 in chloroform EXAMPLE ,4

The l7fl-tetrahydropyranyl ether of 3:3-ethy lenedioxy- 17fi hydroxy-17u-pregn-5-en-20-yne, prepared as described in Method -'('b) of Example I, was n-butylatedand the crude product treated with hot aqueous ethanolic oxalic EXAMPLE 5 no x11) (XII, where R=CH l9-nor-17a-pregna-1 3 1 5 10 -trien-2 0-yne-3: 17s diol (2 g.) in dry tetrahydrofuran (17 ml.) and 2:3-dihydropyran (5 ml.) was treated withphosphorus oxychloride (0104 ml.). After 2 /2 hours at room temperature, the

9 mixture was treated with anexcess of very dilute aqueous sodium bicarbonate and the product isolated with ether. Crystallised from aqueous acetone containing a trace of pyridine, the 3:l7 3-bis-tetrahydropyranyl ether of 19- nor 17wpregna-1z3 :(10)-trien-20-yne-3 l7p-diol formed needles, M.P. 155 to 157 C.

The foregoing compound .(1 g.) in dry ether (30 ml.) was added over 30. minutes to'a stirred solution of ferric nitrate (0.05 g.) and lithium (0.2 g.) in liquid ammonia (50 ml.) maintained at a temperature just below the boil ing point. The mixture Was stirred for 2 hours, methyl iodide (3 ml.) in ether ml.) added over 30 minutes. and the stirring continued for a further 3 hours. Ammonium chloride was added, and the ammonia allowed to evaporate. The product, isolated with ether, was heated under reflux for 30 minutes with toluene-p-sulphonic acid (100 mg.) in ethanol (12 ml.). Chromatography of the product, gave 21-methyl:19-nor-17a-pregna-1 :3 5( 10) trien-20-yne-3z17fi-dioliwhich crystallised (as a mono hydrate) from aqueous methanol, in plates, M.P. 110 C., 11 +3 (c,O .37 in chlorofrm). t

(EXAMPLES 21-ethyl-I9-nof-17u-pregrta-1 :3 :5 (10) -trien-20- yne-3 :1 7 9-diol (Formula XII, where R=C H The aboveficompound was prepared by the procedure describedin Example 5, ethyl iodide being employed in place of methyl iodide at the alkylation stage. When crystallised from aqueous methanol, the compound sep (Formula XI I, where R==n-propyl) The above compound .was prepared by the procedure described in Example 5, n-propyl iodide being used in place of methyl iodide at thealkylation stage. Purified from ether/hexane, the compound formed needles, M.P. 107 10 108".C., [q=1 5: (0,033 chloroform).

. yne-3z17fi-diol (Formula XII, whereR=n-butyl) a {EXAMPLE 9 I A suspension or .6s-methy1-17a-pregm20-yne-3m5a: 17fi-t1'iol (1.2 g.) prepared, for example, by the process set forth in' oopending application Serial No. 587,447, filed May 28, 1956 in dry ether ml.)..and 2:3-dihydropynan (2 ml.) was treated with phosphorus oxychlo ride (5 drops). After 1 hour the homogeneous solution was washed with dilute aqueous sodium bicarbonate,- Water, dried, and the solvent removed :under reduced pressure. The residue (2.15 g.) consisted. of a clear gum, and was used without further purification for the next stage of-the process.

The foregoing product (10 g.) in dry ether ml.) was added dropwise over /1 'hour to a stirred solution of ferric nitrate (0.4 g.) and lithium (2.4 g.) in liquid ammonia maintained at a temperature between --30 C. and -40 C. After stirring for a further 2% hours, a solution ofntethyl iodide (2l.rnl.), in dry ether (100 ml.) was added .over 30 minutes. and thestirring continued thereafter for a :further 3hours. 'Ammonium chloride (20 g.).was added to the mixture, and the ammonia allowed to evaporate. .The product was isolated with ether and obtained as a 9.2 g.- of the, product was heated under reflux for. 1 hour with oxalic acid dihydrate (l0'g1) inmethanol (100 ml.) and water (10 ml.) The crystalline, product obtained on concentrating the solution under .reduced pressure was purified from aqueous ethanol to give -65:2l dimethyl-l7a-pregn-20-yne-3p3z5a: l7fl-t-riol in needles MJP. 219 to 221 C. decomp., [ezl -63? (c,0.88 in chloroform).

A solution of the'foregoing triol (3.4 g.) in pyridine (35 ml.) was added to a solution of'chromium trioxide (3 g.) in pyridine (30 ml.) and. themixture allowed to stand overnight; The product, isolated with benzene, was. crystallied from acetone/hexane to give 5a:17B-dihydroxyl-lSfl:2l-dimethyl-17a-pregn-20-yn-3-one in nee dles; M.P. 248 to 250 decomp., [611 -45 (c, 0.82 in chloroform)... t

Asolutionofthe foregoing ketone (1.5 g.) in ethanol (45 ml.) containing concentrated hydrochloric acid (4 drops) was refluxed for 1 hour. "The product obtained on the addition of ,water was purified from aqueous: methanol. 6a:21-dimethyl-17 3hydroxy l7u-pregn-4-en-- 20-yn-3-one formed plates, M.P. 99 to 102 C.

iFOlll'tdt C, 77.2; H, 9.6. C H; O .H O requires C, 77.1;

.ride (0.5 ml.). After 3 hours at room temperature, the homogeneous solution was washed with dilute aqueous potassium bicarbonate, water,:driedover anhydrous sodium sulphate andevaporated to dryness under reduced pressure. The residue (17 g), a clear gum, in dry ether (200 m1.) and tetrahydrofuman (50 ml.) was added dropwise over /4 hour to asuspension of lithami-de (from 3.6 g. of lithium) in liquid ammonia (600 ml.) containing ferricni-trate (0.6"g.). After stirring for a further 2 /2 hours at 30 t 0'--40 "C.,*asolutionof ethyl iodide (30ml) in dry ether 150 ml.) was added over J/z' hour and the mixture was stirred for a further 3 hours at the same temperature. Ammonium chloride (20 g.) was added and the ammonia was allowed to evaporate. Water and ether were added tothe residue, the; organic layer was separated, washed with dilute sulphuric acid,

dilute aqueous potassium bicarbonate, water, dried over anhydrous sodium sulphate and the solvent removed under r educed pressure. The residue (16.6 g.) in methanol (150 ml.) and water (15 ml.) was refluxed with oxalic acid (15 g.) for 1 hour. The resulting solution was concentrated under reduced pressure, diluted with water and extracted with ether. The extract was Washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. Crystallisation of the residual gum from aqueous methanol gave 21-ethyl-6fi-methyl-17a-pregn-20-yne-3B:5a: 175 triol as needles, M.P. 168" t 170 C. or 110" to 112 C. (dimorphous forms), [al -66.2 (c, 0.72 in chloroform).

A solution of the foregoing triol (6.7 g.) pyridine (70 ml.) was added to one of chrominum trioxide (6 g.) in pyridine (60 ml.). The mixture was stirred for 2 hours at room temperature and was then allowed to stand overnight at the same temperature. The product was isolated with benzene and crystallised from aqueous methanol to give a:17B-dihydroxy-21-ethyl-6fl-rnethyll7ot-pregn-20-yn 3-one as needles, M.P. 225 to 227 C., [011 '--44.5' (c, 0.892 in chloroform). V

A' solutionof the foregoing ketone (1.5 g.) in ethanol (45 ml.) containing concentrated hydrochloric acid (4 drops). was refluxed for 1 hour. Concentration of the solution under reduced pressure followed by dilution with water gave afgum which was extracted into ether. The extract was washed with dilute aqueous sodium bicarbonate, water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. Crystallisation of the residual gum from aqueous methanol gave 2l-ethyl-l7B hydroxy-6a-methyl-l7a-pregn-4r en-20-yn-31one as laths, M.P. 74 to 76 C. [Found: C, H, 9-95- CgQHggQz-Hge requires C, H, 9.75%. M.'P. 70. to 73 C. after drying for 7 hours at 0.1 mm. and 55 C. (loss in weight: Found: 4.95. C H O H O requires 4.85%], [001 172 (c, 1.02 in chloroform), R 241 mu, log a. 4.18 (in alcohol).

EXAMPLE 11 21 -n-propyl-I 7 fl-hydroxy da-methyl-l 7u-pfggu-4-en-20- yn-3-dne in dry ether (150 ml.) and tetrahydrofuran (50 ml. was

added over- V; hour to a suspension of lithamide (from 3.6 g. of lithium) in liquid ammonia (600 ml.) containing ferric nitrate (0.6g) and the mixture was stirred for a further 2 hours at 0 to 40 (3.; A solution of n-propyl iodide (30 ml.) in dry ether (150 ml.) was added over V2 hour and the reaction mixture was stirred for a. further 3 hours at the same temperature. The crude product, isolated ether, was refluxed for 1 hour in methanol(150 ml.) and water ('15 ml;)- containingoxalic acid (15 g.).: Concentration of the solution under reduced pressure followed by dilution with water gave a guru which was extracted into ether. The ether solution was'washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The gummy product crystallised from aqueous methanol tov give 2l-n-propylefifiimethybl7u-pregn-20 yne13/3:5a: 17fi-.triol as needles, MR. 177;;to 179"" G., or 92 to C- gicrnhq s rms). Isle 146.9 0.82 shl qtv w- A sq t i t e q s q lls Q 9 m in PY i' dine (1011111.) as-ad edtcy e chmmi cxide.

( 8 g.) in pyridine 1 .0 nil-f and the mixture was stirred for 1 hours at room temperature. After standing overnight at the same temperature, the productwas isolated f om the solution with z'e r1 e. w ,EvaporatiQn of the bruises att acted. r alliuer'esidtw (M-B- 1 19 r94" 3.) hic 9 p r iiva i at o iequso s me an l. yielded 6-methy1 21 n-propyl-3-oxo-17a-pregn-20-yne- Sml'ip-diol in blades, M.P. 176 to 178 3.,

[0611 +407 (c, 0.78 in chloroform). This was dissolved'in methanol (25 ml.) containing concentrated hydrochloric acid (2 drops) and the solution was refluxed for 1 hour.

Concentration under reduced pressure followed by dilution with Water gave a gum which was chromatographed basic dose is 0.5 milligram, although much larger doses (e.g. at least 2.5 milligrams) or smaller doses may be given if desired, the following. types of preparations may serve to illustrate typical formulations:

EX M?L Tablets Zlzfitb h Q y-6 -me y1- -p m4- n- 20-yn 3-one 0.5 Lact e g- 83-0 Magnesium stearate 1.0

Maize starch (as 10 percent paste), asu fiicient quantity. Dried maize starch, sufiicient to produce 98.0 mg.

The first two ingredients are mixed and granulated with starch paste followed by drying at 50 C. The resultant granules are processed through a 20 mesh sieve and the lubricant (magnesium 'stearate') added, together with suflicient dried starch to produce the required weight. Tablets each weighing 97- mg. are compressed from this mixture.

EXAMPLE 13 Capsules s- 21-ethyl 1713 hydroxy-6a-methyl-l7ot-pregn-4-en- 20-yn-3-one 0.5

Lactose, a suflicient quantity. I

0.5 mg. of the finelysubdivided steroid is triturated with lactose to produce a volume of powder which just fills a two piece hard. gelatin capsule.

' E A.M1 'I. E14v P rente a salutiqn n. oi

21-ethyl 17,8 hydroxy-6a-methyl-l7a-pregn-4-en' 20-yn-3-one" ;.mg 0.5

Ethyl oleate (or a suitable fixed oil), sufiicient to produce 1.0 ml.

The ethyl oleate is sterilised by heating at 160 C. for 1 hour and allowed to cool, To this is added the benzyl alcohol, with aseptic precautions. The steroid is dissolved in the warm mixture at about 50 C. and the resultant solution clarified by passing it through a previously sterilised No. 2 sintered glass filter. The filtrate is sub-divided into suitable containers which are finally subjected to 100 C. dry heat for 1 hour.

EXAMPLE 15 V 6 :21 -dimethyl-1 7a-pregn-5 en-20 yne-3fid 7fl-di0l Acetylene purified by passing through an acetone/C0 trap and two wash bottlescontaining cpncentrated H was bubbled through dry ether ml.) in a 1 litre benzene (10 ml.) was added dr'op'wise over 30 minutes and stirring continued for hours, acetylene being bubbled through continuously.

The reaction mixture was acidified with saturated ammonium chloride solution containing a little hydrochloric acid and the product isolated with ether. Crude 6- methyl-17a-pregn-5-en-20-yne-3fl:17,6-diol was obtained as a solid of M.P. 190 to 194 C. Purification from a grgjallcvolume of methanol gave plates, MP. 203. to

The foregoing diol in dry tertahydrofuran ml.) and 2:3-dihydropyran'(3 ml.) was treated with phosphorus oxychloride (0.02 ml.). The mixture was stored overnight at room temperature and then poured into water (300 ml.) containing a little dissolved sodium bicarbonate. The oil thus obtained was isolated with ether and recrystallised from acetone containing a trace of pyridine. The bistetrahydropyranyl ether of 6-methyll7ct-pregn-i-en-20-yne-3fl:17fl-diol was obtained as fine needles, M.P. 178 to 180 C. [a] --122.2 (c, 0.450 in chloroform).

The bis-tetrahydropyranyl ether of 6-rnethyl-l7apregn-5-en-20-yne-3B:l7 3-diol (700 mg.) in dry ether (40 ml.) was added to a stirred suspension of lithamide prepared from lithium (400 mg.) in liquid ammonia (75 ml.) (with 50 mg. ferric nitrate added) at --35 to 40 C. After stirring 2% hours methyl iodide (2.5 ml.) in ether ml.) was added over 25 minutes and stirring continued thereafter for a further 3 hours. Excess lithamide was decomposed by means of ammonium chloride and the ammonia allowed to evaporate overnight. The product was isolated with ether. Crystallisation from aqueous acetone containing at trace of pyridine gave the hydrate of the bis-tetrahydropyranyl ether of 6:21-dimethyl 17a pregn-5-en-20-yne-3B:17,3-diol as needles, M.P. 160 to 161 C. [01], ---117.0 (0, 0.282 in chloroform).

The bis-tetrahydropyranyl ether of 6:21-dimethyl-l7apregn-5-en-20-yne-3/3:17,8-diol dissolved in ethanol (100 ml.) was treated at the boil with a hot solution of oxalic acid dihydrate (1.4 g.) in water (50 ml.) and the boiling continued for 1 hour. Diluting to turbidity and long standing gave 6:21 dimethyl 17a pregn-5-en-20-yne- 3,8:l7fl-diol as needles, M.P. 164 or M.P. 111 to 112 C., [(11 --102.6 (c, 0.604 in chloroform).

EXAMPLE l6 Pharmaceutical preparations from 6a:21-dimethyl-17phydroxy-l 7a-pregn-4-en-20-yn-3-one Tablets 8- 6az2l-dimethyl 17 8 hydroxy-17a-pregn-4-en-20- yn-3-one 5 Lactose 81.4 Magnesium stearate 0.972 Maize starch, to 97.2 mg.

The first two ingredients are mixed and granulated with 10% starch paste followed by drying at 50f C. The resultant granules are processed through a mesh sieve and the lubricant (magnesium stearate) added, together with sufficient dried starch to produce the required weight.

Tablets each weighing"97.2 mg. are compressed from this Capsules 6at21 dimethyl-17fl-hydroxy-l7a-pregn-4-en-20-yn- 3-0118 Lactose, a suificient quantity.

5 mg. of the finely subdivided steroid hormone is triturated with lactose to produce a volume of powder which just fills a two piece hard gelatin capsule.

We claim; 1 v

2. 5a:176-dihydroxy-6B:ZI-dimethyl 17a pregn-20- yn-3-one.

triol.

4. 5a:17fl-dihydroxy-2l-ethyl-Gfl-methyl 17a pregn- 20-yn-3-one.

5. 6:21-dirnethy1-17a-pregn-5-en-20-yne-3B:17 B-diol.

7. 2l-ethyl-l7fl-hydroxy-6a-methyl 17a pregn-4.-en 20-yn-3-one.

8. A therapeutic composition in dosage unit form having progestational properties, comprising 2l-ethyl-l7fl-hydroxy-fia-methyl-l7a-pregn-4-en-20-yn-3-one and at least one member selected from the group consisting of a sugar, starch, and magnesium stearate.

9. A therapeutic composition in dosage unit form having progestational properties, comprising 6az2l-dimethyll7B-hydroxy-17u-pregn-4-en-20-yn-3-one and at least one member selected from the group consisting of a sugar, starch and magnesium stearate.

10. A process for the preparation of 2l-alkyl derivatives of 17fl-hydroxy-17a-pregn-20-ynes which process comprises condensing a 17fl-hydroxy-l7a-pregn-20-yne with 2:3-dihydropyran to give a 17 3-tetrahydropyranyl ether, reacting said ether with an amide of an alkali metal in liquid ammonia to provide the corresponding C alkali metal derivative of said ether, condensing said alkali metal derivative with an alkyl derivative selected from the group consisting of alkyl chlorides, bromides, iodides and sulfates to provide the corresponding C -alkylated tetrahydropyranyl ether, and hydrolizing the product by treatment with a source of hydrogen ions to regenerate the l7fl-hydroxyl group.

11. A process for the preparation of a 21-a1kyl derivative of l7fl-hydroxy-l7a-pregn-20-yn-3-one, comprising ketalizing a 17p-hydroxy-17-u-pregn-20-yn-3-one to provide the corresponding 3:3-ethylenedioxy derivative, condensing said 3:3-ethylenedioxy derivative with 2:3-dihydropyran to provide a 17,8-tetrahydropyranyl ether of said 3:3-ethylenedioxy derivative, reacting said ether with an amide of an alkali metal in liquid ammonia to yield the corresponding C -alkali metal derivative of said ether, condensing said alkali metal derivative with an alkyl derivative selected from the group consisting of alkyl chlorides, bromides, iodides and sulfates to provide a 2l-alkylated 17fi-tetrahydropyranyl ether and treating said 21-alkylated 17fl-tetrahydropyranyl ether with dilute ethanolic oxalic acid to regenerate the 17 fi-hydroxyl group and the 3-oxo group.

12. 21-alkyl derivatives of l7 3-hydrox y-17a-pregn-20- yne having the general formula OH *"OECR 1 5 Y 16 Where R is an alkyl group containing from 1 to 4 carbon Rferences Cited in the file of this patent atoms, and R is selected from the group consisting of I UNITED STATES PATENTS 21,276,547 Ruzicka Mar. 17, 1942 2,280,236 Inhoffen et a1. Apr. 21, 1942 2,318,105

Ruzickaf t May 4, 1943 2,843,609' 2,845,381

Colton July 15, 1958 Tindall July 29, 1958 UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,939,819 June 7, 1960 Suzanne Patricia Barton et a1.

It is hereby certified that error appears in the above numbered atent requiring correction and that the said Letters Patent should read as corrected be ow.

Column 2, lines 53 to 63, Formula (II) should appear as shown below instead of as in the patent:

column 3, lines 34 to 44, Formula (IV) should appear as shown below instead of as in the patent:

0 %--o i on column 5, line 61, for EAMPLE read -EXAMIPLE-; line 62, for -ethyZ-, read -methylsame column 5, lines 65 to 74, Formula (XI) should appear as shown below instead of as in the patent:

--oz on column 15, lines 8 to 14, the last two groups should appear as shown below instead of as in the patent:

no and HOW a Signed and sealed this13th day of June 1961.

Attest:

ERNEST W. SWIDER, DAVID L. LADD,

Attesting 077 5007. Gammiasiomr of Patentl. 

